Last updated 2mo ago
A 42-year-old is diagnosed with colorectal cancer. His tumor shows microsatellite instability (MSI-high) and loss of MLH1/PMS2 on IHC. Family history reveals colon cancer in his father at 48 and endometrial cancer in his sister at 45.
AD; mismatch repair (MMR) genes
- MLH1 (~40%), MSH2 (~35%), MSH6 (~15%), PMS2 (~10%)
- EPCAM deletions affect MSH2 expression
Cancer Risks (lifetime):
- Colorectal: 40-80%
- Endometrial: 25-60%
- Ovarian: 4-24%
- Gastric, urinary tract, small bowel, brain, sebaceous tumors
- Right-sided colon cancers
- MSI-high/dMMR tumors (IHC, MSI testing)
- Multiple primary cancers
- Amsterdam criteria, Bethesda guidelines
- Muir-Torre syndrome (sebaceous tumors) - MSH2
- Turcot syndrome (brain tumors) - MLH1, MSH2
- Amsterdam II criteria ("3-2-1": 3 affected relatives across 2 generations with 1 diagnosed before age 50, one a first-degree relative of the others, FAP excluded) and the Bethesda guidelines flag who to screen, but clinical criteria miss many cases
- Universal tumor screening with MMR immunohistochemistry (loss of MLH1, MSH2, MSH6, or PMS2) and/or microsatellite instability (MSI-high) testing is the standard reflex screen on colorectal and endometrial tumors
- Isolated MLH1/PMS2 loss warrants BRAF V600E testing and MLH1 promoter hypermethylation analysis to distinguish sporadic from germline causes before genetic testing
- Confirm with germline testing of the MMR genes and EPCAM; EPCAM deletions silence MSH2
- Colonoscopy every 1-2 years starting age 20-25
- Consider prophylactic hysterectomy/BSO after childbearing
- Aspirin may reduce risk
"Just as Lunch passes through your colon, Lynch is the most common cause of hereditary colon cancer." Lunch = Lynch.
"If I miss My Lunch Hour, HuNger Persists in my Colon & stomach": Miss = Mismatch repair, Lunch = Lynch, My Lunch Hour = MLH1, Colon and stomach cancer.
"3,2,1" for Amsterdam criteria: 3 family members, 2 generations, 1 person diagnosed with CRC at <50 years old.
"Please! More Mish-Mash for Lunch": PMS, MLH1/3, MSH2, MSH3/6, the mismatch repair genes. If it has "MS" in the name (MSH, PMS) or starts with "M", it is a MiSmatch repair gene.